REGULATORY COMPLEXITIES IN HIGH POTENT DRUGS: REQUIREMENTS FOR GLOBAL REGULATORY COMPLIANCE

Dr. Bhaswat S. ChakrabortySr. VP & Chair, R&D Core CommitteeCadila Pharmaceuticals Ltd., Ahmedabad

Presented at the CPhI UBM High Potent Drugs 2013

Mumbai, January 23, 2013

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CONTENTS Understanding the complex regulatory requirements

with respect to manufacturing & research & development

Establishing an overview of OSHA and European classification to stay updated with global regulatory standards

Determination of ADEs which forms a key component of the Risk-maPP approach to manage the risk of cross product contamination in multi-product facilities.

Clarifying the regulatory concerns on multiple High Potent Drugs being manufactured in the same facility to ensure compliance 2

DEFINITION OF HIGH POTENT (HP) DRUGS Potency is a measure of drug activity expressed in terms of

the amount required to produce an effect of given intensity A highly potent (HP) drug evokes a larger response at low

concentrations, Lower potency drug evokes a smaller response at similar

concentrations A HP drug has

occupational exposure levels (OELs) of less than 10 μg/m3 of air after applying appropriate uncertainty factors or

A daily therapeutic dose of 10 mg/day, or A dose of 1 mg/kg/day in laboratory animals producing

serious toxicity All HP drugs are, therefore, potentially hazardous drugs and

along with drug handling and manufacturing standards, occupational safety and environmental issues are paramount

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DEFINITION OF A HAZARDOUS DRUG Exhibits one or more of the characteristics in humans

or animals: Carcinogenicity Teratogenicity Reproductive toxicity Organ toxicity at low doses Genotoxicity Environmental damage or pollution

National Institute for Occupational Safety and Health (NIOSH) provides a list of hazardous drugs, e.g., Antineoplasitc (Methotrexate, topotecan, irinotecan, vinorelbine) Antiviral (Ganciclovir) Hormone (Progesterone) Misc. (Cyclosporin) 4

The performance-based exposure control limits (PBECL) are very popular in Pharma industries

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Category 1: compounds are low potency with higher dosage levels

Category 2 compounds: moderate acute or chronic toxicity, but theireffects are reversible

Category 3 compounds: have elevated potency, with high acute or chronic toxicity; these effects may be irreversible

Category 4 compounds: have high potency and extreme acute and chronic toxicity, cause irreversible effects and are likely to be strong sensitizers, with poor or no warning properties and a rapid absorption rate

All HP products are category 3 or 4, based on their cumulative risk factors; regulatory requirements for containment and protection vary among the categories

HISTORY OF CONTROL BANDING OF DRUGS & PHARMACEUTICALS The concept of using categorization schemes for managing

chemical handling was developed in late 80’s The system of severity of hazard, and the controls required to

reduce exposures to acceptable levels by US Pharma companies in early 90’s

Hazard categorization scheme by British Pharmaceutical Industry in mid-90’s

COSHH Essentials by Health and Safety Executive (HSE), UK: late 90’s

The International Labor Organization toolkit for less-developed countries, early 2000’s

Other recent guidances by ACGIH, AIHA, ILO, IOHA, NIOSH, OSHA and WHO for control banding

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WHY LEARN ABOUT REGULATORY REQUIREMENTS OF HP DRUGS? As a novel drug (pre-IND or IND stage), one does not

what kind of impact this drug will have on human body At occupational exposure levels of <10 μg/m3, these

drugs are (or potentially) toxic or highly toxic to the operator/handler

Could be cytotoxic, teratogenic or genotoxic A lot of uncertainty about safety of the processing

environment (common sense is not enough) In hazardous situations, the paradigm is “highly potent

until proven otherwise” Facilty & equipment design, writing SOPs, BMRs, reports Product control, dust control, yield control… 7

REGULATORY REQUIREMENTS They are complex as several different laws, acts

and regulations cover same and different aspects

A reductionist approach may not work for a thorough insight but cGMP product protection & personnel safety are two main focal points

Handling, Equipment, Containment, Engineering, Administrative, Safety & Environmental are the main regulatory issues

Covered by 21 CFR part 210 (211), 29 CFR 1910, ICH Q7A, OSHA (& NIOSH), Controlled Compound Act and many other overlapping regulations and guidances

No single document tells you exactly what to document However, especially for manufacturing, the approach

and milestones are cGMP appropriate for HP drugs

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BASICS OF CGMP

SOPs are clearly and instructionally written and practiced in letter & spirit

Facilities are well designed to contain cross-contamination and mix ups

Build validated quality at every step of manufacturing

Well trained personnel Manufacturing processes are well defined and

controlled Documentation of all steps, tests and deviations Practice, learn, update, practice, learn, update… 9

THE GLOBALLY HARMONIZED SYSTEM OF CLASSIFICATION AND LABELING OF CHEMICALS (GHS)

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Source: Health and Safety Executive (HSE), UK

EXPOSURE Exposure can occur by:

Aerosolization, contact with contaminated surface, volatility Inhalation, skin contact, skin absorption, ingestion, and

injection. Inhalation, skin contact, and skin absorption are the

most likely to occur

Evidence of exposure Mutagenicity Developmental and Reproductive Effects Cancer

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RISK-MAPP Risk-based Manufacture of Pharmaceutical Products, A Guide

to Managing Risks Associated with Cross Contamination (Risk-MaPP), 2010 Volume 7 of Baseline Guide series by International Society

of Pharmaceutical Engineers (ISPE) Provides a scientific, risk-based approach to managing the

risk of cross product contamination in multi-product facilities Allows determination of Acceptable Daily Exposure Limits

(ADEs) ADEs are based on the toxicological and pharmacological

properties of the specific API Risk-MaPP defines the ADE of an API to be the estimated

dose that is unlikely to cause an adverse effect if an individual is exposed to the API by any route, at or below this dose every day for a lifetime 12

CALCULATION OF ACCEPTABLE DAILY EXPOSURE (ADE)

ADE = (NOAEL x BW) / (UFC x MF x PK) where:

BW = Body Weight (kg) [default for an adult is 50 kg]; UFC = Composite Uncertainty Factor; MF = Modifying Factor; and PK = Pharmacokinetic Adjustment(s)

In cases where a NOAEL is not available, a LOAEL may be used. In the event that a human dose is used in a derivation, the NOAEL

(or LOAEL or Lowest Therapeutic Dose) may be expressed as mg/day and the BW factor becomes unnecessary

Usually ADE< 10 OEL

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ADE DEVELOPMENT PROCESS Identification of the hazard

Comprehensive review of readily available animal and human (clinical and tox) data to determine the critical effect for ADE

Assessment of the dose-response relationship Once the critical endpoint(s) are determined, LOAEL &

NOAEL are for threshold effects; for non-threshold effects, such as cancer, level of acceptable risk is defined

Calculation of the ADE After selecting a critical effect, uncertainty factors are

applied to calculate an ADE Usually range from 1 to 10 More than one endpoint may be chosen as a critical effect

and leading to multiple calculations Limit with the fewest sources of uncertainty is often

considered appropriate Documentation

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MANUFACTURING MULTIPLE HP DRUGS IN THE SAME FACILITY 1. Robust site policy and system for administrative and

engineering standards, controls and practices for HP compounds

2. Process isolation through area separation, isolators, laminar flow hoods, single pass filtered exhausts, -ve pressure differential in compound handling areas… (focus on the entire facility while preventing cross contamination)

3. Determination of OEL in order to effectively and efficiently establish proper engineering controls, administrative controls, policies, procedures and cleaning verifications

4. Verifying the effectiveness of the containment control strategy by an Industrial Hygiene monitoring of employees

5. Other containment and operational measures that are adequate for preventing cross contamination

6. One set of specifications may not stop all cross contaminations

Source: Calkins (2010)Bioprocess Int, Sept. 2010;Doherty P (2012). CROs/CMOs, Chemistry Today, 30, July/Aug

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ENGINEERING CONTROLS Closed inline sampling systems, continuous bag

systems, isolator/glove box technology, split butterfly valves, and rapid transfer ports to ensure a properly contained system

Engg. control approaches begin with the ventilation, ensuring that an engineered local exhaust system is effective to 100 μg/m3

Laminar flow hoods may be effective between 50 to 100 μg/m3 and directionalized laminar flow booths may be effective to 50 μg/m3

The greatest risk is the solid dry powder form; therefore a lot of attention is paid to the charging system and drying See possibility of something like soft gel The most commonly overlooked area for exposure risk is

associated with degowning practices16

Source: Doherty P (2012). CROs/CMOs, Chemistry Today, 30, July/Aug

THE SYSTEM FOR CONTAMINATION PREVENTION Establish an OEL or an exposure control banding

system For novel compound, estimate a potency to assign

an OEL Can be developed from comparison of NOEL or LOEL data

of similar compounds (at clinical stage one can get a better estimate of true

potency) For given potency category, document the site policy

re: Engineering controls, administrative controls and personal

protective equipment for handling that potent compound Its handling and quality control

Source: Doherty P (2012). CROs/CMOs, Chemistry Today, 30, July/Aug

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SAFETY MANAGEMENT CONTROLS

Safety in handling HP drugs apply to Personnel in Research & Development, Manufacturing, Pharmacy

and nursing, Physicians, Environmental services, Shipping and receiving, Veterinary, Waste management …

Carefully considered site policy or procedure that establishes the containment strategy associated with each potency category

Identify required personal protective equipment, gowning and degowning requirements, cleaning requirements and procedures, and so on.

The point of this practice is to have a well-established practice on how to handle a potent compound and avoid having to make decisions on a case by case basis. eg, for a decision on how a lab handles a 100 ml sample of a

0.1 percent solution of a HP drug, category 4 will have more precautions than a category 2 drug

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CROSS-CONTAMINATION PREVENTION: SHARED FACILITIES Remember, the first principle of containment is: physical separation

and isolation of unit operations Cross contamination from the processing environment must be

prevented By protecting employees from spreading cross contamination into other drugs/

products

Through equipment designs, engineering and administrative controls Strict SOP for handling HP compounds

e.g., no open handling of dry powders with a potency of category III or higher Specialized containment equipment

e.g., isolators will have advertised containment levels <1 μg/m3

Monitoring containment with a drug is more rigorous e.g., naproxen Na gives a more stringent test of containment than does lactose

Containment levels are highly dependent on operational practices e.g., low exposures inside a booth but higher exposures during removal of gloves

and/or degowning Usually containment level demonstrated for one HP compound in a

equipment may not apply to another compound in the same equipment

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CROSS-CONTAMINATION PREVENTION: SHARED EQUIPMENTS For R&D or early small scale work, use stringent disposable

or low cost dedicated equipment to avoid extensive and costly cleaning

With scale up, cleaning SOPs have to be developed HP compounds must be neutralized and reduced to a

negligible amount (very expensive) Calculate actual Maximum Allowable Carry Over (MACO) for each HP

For many HP compounds to be manufactured in a shared equipment, cleaning analytical test methods and SOPs must be developed. Review 3 successive trials of sampling and analysis of residues on the

wetted surfaces of the manufacturing equipment cleaning validation trials will include: visual inspection assessment, rinse

residue assessment, residual swab assessment, microbial assessment, dirty equipment hold time, calibration & analytical method validation, and training record verification

Source: Doherty P (2012). CROs/CMOs, Chemistry Today, 30, July/Aug

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TYPES OF MAXIMUM ALLOWABLE CARRY OVER (MACO)1. Dosage MACO - based on a normal therapeutic dose of

Product A (previous), the maximum daily dose of Product B (next) and the minimum batch size of Product B (next)

2. Toxicology MACO - based on toxicological information (LD50 or OEL) of product A (previous), normal daily dose of Product B (next), safety factors based on if Product B is administered topically, orally or parenterally, and minimum batch size of Product B (next)

3. General Limit MACO – typically based on an assumed 10 ppm limit. Use of the general limit MACO should only be used when no data yet exists and such use should be justified or explained

The MACO limits established above are used to calculate Acceptable Swab Residue and Acceptable Rinse Residue limits.

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ISOLATORS Often more stringent than Biological Safety

Cabinets Class III Cabinet with a ventilated controlled environment

with fixed walls, floor, and ceiling. Operator access through fixed glove ports Supplies entry through an air lock Must be able to be sanitized and decontaminated Ventilated glove box.

Compounding Aseptic Containment Isolator (CACI) Designed to meet the requirements of both an aseptic

isolator and an containment isolator Used for aseptic hazardous drug preparation Exhaust air removed from cabinet by properly designed

building ventilation. 22

High potency pilot plants

Weighing isolator Cytotoxic solids handling zone

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MATERIAL SAFETY DATA SHEETS (MSDSS)1. IDENTIFICATION OF THE SUBSTANCE /

PREPARATION AND COMPANY UNDERTAKING

2. COMPOSITION / INFORMATION ON INGREDIENTS

3. HAZARDS IDENTIFICATION4. FIRST – AID MEASURES5. FIRE FIGHTING MEASURES6. ACCIDENTAL RELEASE MEASURES7. HANDLING AND STORAGE

8. EXPOSURE CONTROL / PERSONAL

PROTECTION

9. PHYSICAL AND CHEMICAL PROPERTIES10. STABILITY AND REACTIVITY11. TOXICOLOGY INFORMATION12. ECOLOGICAL INFORMATION13. DISPOSAL CONSIDERATIONS14. TRANSPORT INFORMATION15. REGULATORY INFORMATION16. OTHER INFORMATION

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CONCLUDING REMARKS There are no unique regulations in major jurisdictions which

specifically address the manufacture of highly potent pharmaceuticals

R&D level may require higher containment program as unknowns are more

Figure out Acceptable Daily Exposure Limits for all HPs Handling, Equipment, Containment, Engineering,

Administrative, Safety & Environmental are the main areas to be competent in and document

Consider outsourcing when you don’t have a “beyond doubt” facility & capability

For manufacturing of HP drugs, have a cGMP mindset, practice, learn, update, practice further….

For manufacturing Multiple HP Drugs in the Same Facility, map & design the entire facility, not just the production area

Use appropriate engineering and administrative controls Document extensively

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THANK YOU VERY MUCH

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